Phys · rheumatological
Complement Deficiencies AND Recurrent Infections
Also known as Complement Deficiencies AND Recurrent Infections · C1q deficiency · C2 deficiency · terminal complement deficiency · properdin deficiency · factor I deficiency · factor H deficiency · hereditary angioedema · C1 inhibitor deficiency
Consultant-physician depth guide to complement deficiencies and recurrent infections — classical pathway defects (C1q, C1r/s, C2, C4) with autoimmune risk, lectin pathway defects with encapsulated bacteria, alternative pathway (factor D, factor P/properdin) with Neisseria and invasive meningococcal disease, terminal pathway C5-C9 with Neisseria, factor I and factor H deficiency with atypical HUS and C3 glomerulopathy, hereditary angioedema (C1-INH SERPING1) with acute and prophylactic therapy (C1-INH concentrate, icatibant, ecallantide, lanadelumab, berotralstat), vaccination strategies, and the workup of recurrent infection with low C3/C4. Structured for FRACP DWE/DCE, MRCP and ABIM preparation.
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Red flags
- Acute angioedema in a patient with low C4 and normal tryptase — hereditary angioedema; do NOT give adrenaline alone (it does not work); give C1-INH concentrate 20 units/kg IV or icatibant 30 mg SC
- Invasive meningococcal disease — suspect terminal complement deficiency (C5-C9) or properdin deficiency; check CH50 and AH50 post-recovery
- Recurrent infections with encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis) — consider complement deficiency as well as hypogammaglobulinaemia
- C1q deficiency presenting as early-onset SLE — affects about 90 percent of patients with homozygous deficiency
- C3 deficiency — recurrent pyogenic infections and immune-complex disease; rare but severe
- Factor H or factor I deficiency in a child with atypical HUS — needs urgent complement genetics and eculizumab
Complement Deficiencies AND Recurrent Infections
The answer first
Complement deficiency syndromes are rare but high-yield in physician examinations because they reveal a clear pathophysiology-to-bedside logic: which pathway (classical, lectin, alternative, terminal) is defective dictates which infections, autoimmune complications, and angioedema phenotypes follow. [1]
A physician-level answer rests on four pillars: [1]
- Pattern-recognition from the clinical syndrome. Recurrent sinopulmonary infection with encapsulated organisms points to classical pathway (early C1q/C2/C4) defect or hypogammaglobulinaemia; recurrent or invasive Neisseria points to terminal pathway (C5 to C9) or properdin deficiency; angioedema without urticaria with low C4 points to hereditary angioedema (C1-INH deficiency); atypical HUS points to alternative-pathway dysregulation (factor H, factor I, factor B, C3 mutations). [1]
- CH50 and AH50 as first-line screening tests. CH50 tests classical and terminal pathways; AH50 tests alternative and terminal pathways. Both near-zero → terminal deficiency; CH50 low AH50 normal → classical; CH50 normal AH50 low → alternative; both low but non-zero → C3 deficiency. [11]
- Mechanism-based treatment. Hereditary angioedema needs C1-INH concentrate, icatibant, or ecallantide — not adrenaline. Terminal pathway deficiency needs lifelong meningococcal vaccination (quadrivalent and MenB), antibiotic prophylaxis, and patient education for prompt treatment of suspected infection. Factor H/I deficiency with atypical HUS needs eculizumab. [7] [8]
- Look for autoimmune overlap. C1q, C1r/s, C2, C4 deficiency confer a high lifetime risk of SLE; C2 deficiency is the most common complement deficiency in Caucasians and a recognised cause of SLE in young women. [2] [3]
DWE high-yield: Three classic associations — C1q deficiency and SLE (about 90 percent lifetime risk), terminal pathway deficiency and Neisseria (5000 to 10 000 fold risk of invasive meningococcal disease), factor H or I deficiency and atypical HUS. The simple "low C3 low C4" pattern indicates classical pathway activation (SLE, immune complex, cryoglobulinaemia); "low C3 normal C4" indicates alternative pathway (C3 glomerulopathy, aHUS, post-infectious). [1] [2]
References12ShowHide
- [1]Grumach AS, Kirschfink M Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol, 2014.PMID 25037634
- [2]Coss SL, Zhou D, Chua GT, et al. The complement system and human autoimmune diseases. J Autoimmun, 2023.PMID 36535812
- [3]Bowness P, Davies KA, Norsworthy PJ, et al. Hereditary C1q deficiency and systemic lupus erythematosus. QJM, 1994.PMID 7922299
- [4]Vyse TJ, Späth PJ, Davies KA, et al. Hereditary complement factor I deficiency. QJM, 1994.PMID 7922290
- [5]Nielsen HE, Koch C Congenital properdin deficiency and meningococcal infection. Clin Immunol Immunopathol, 1987.PMID 3608246
- [6]Colobran R, Franco-Jarava C, Martín-Nalda A, et al. Novel Mutations Causing C5 Deficiency in Three North-African Families. J Clin Immunol, 2016.PMID 27026170
- [7]Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy, 2022.PMID 35006617
- [8]Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med, 2010.PMID 20818888
- [9]Trendelenburg M Autoantibodies against complement component C1q in systemic lupus erythematosus. Clin Transl Immunology, 2021.PMID 33968409
- [10]Rajabi E, Kheirabadi MC, Olyaei NA, et al. Complete Complement Factor I (CFI) deficiency: a systematic review of forty-nine patients including three novel cases. BMC Immunol, 2025.PMID 40713518
- [11]McMurray JC, Schornack BJ, Weskamp AL, et al. Immunodeficiency: Complement disorders. Allergy Asthma Proc, 2024.PMID 39294906
- [12]Westberg J, Fredrikson GN, Truedsson L, et al. Sequence-based analysis of properdin deficiency: identification of point mutations in two phenotypes. Genomics, 1995.PMID 8530058